Mitochondrial myopathies are diseases of varying severity related to dysfunction of the mitochondrial respiratory chain. The mechanisms by which mitochondrial dysfunction cause impaired muscle function are poorly understood, and effective treatment is lacking. Preliminary data indicate that changes in intracellular calcium (Ca2+) handling play a key role in the contractile dysfunction, and a novel way to treat these diseases has been postulated. The overall goal of this translational project is to determine the mechanisms by which mitochondrial myopathy exerts its effects on muscle function. The project has three specific aims: 1) Examine global Ca2-i- handling and force in isolated skeletal muscle cells of mouse models of mitochondrial myopathy and their controls. Measure the expression of Ca2+ handling proteins in the mouse disease models and their controls as well as in muscle biopsies from patients with mitochondrial myopathies. 2) Examine the changes in mitochondrial Ca2+ in models of mitochondrial myopathy and their relation to opening of the mitochondrial permeability transition pore (MPTP). 3) Determine whether the defects in muscle function and Ca2+ handling can be reversed by inhibitors of mitochondrial Ca2+ uptake via the MPTP. Mitochondrial disorders show great variability in clinical features and genetic causes and in addition to muscle dysfunction have been implicated in numerous diseases, including type 2-diabetes and heart failure. Taken together they are regarded as the most common group of inborn errors of metabolism and it is therefore important to elucidate mechanisms of defects and treatments. Results of the proposed study will contribute such information.